(1). Field of the Invention
This invention relates to a process for the preparation of isoflavones and in particular formononetin. The process involves reaction of a 2-hydroxy-deoxybenzoin with N,N'-dimethyl (chloromethylene)ammonium chloride to form the isoflavone. This invention particularly relates to either a "one pot" or a two step process involving the initial formation of 2,4-dihydroxy-4'-methoxydeoxybenzoin followed by its conversion to formononetin.
(2). Description of Related Art
Isoflavones are important compounds which are used for a variety of biological purposes. In particular, formononetin (MYCOFORM, VamTech, L.L.C., okemos, Mich.) is a potent vesicular-arbuscular mycorrhizal stimulating compound (U.S. Pat. Nos. 5,085,682, 5,125,955 to Safir et al; Taiwan Patent No. 60604 to Safir et al; U S. Pat. No. 5,691,275 to Nair, et al; Nair, M. G., et al, Applied and Environmental Microbiology 57:434 (1991); Siqueira, J. O., et al., Plant and Soil, 134:233 (1991); and Siqueira, J. O., et al., The New Phytologist, 118:87 (1991)). Formononetin is under extensive field trials on corn, soybean and horticultural crops around the world. The prior art procedures for the production of isoflavones are not economical.
The synthesis of formononetin, which is the preferred isoflavone and is representative, from the corresponding chalcone is a known process. The method (Sekizaki, H., et al., Studies on Zoospore Attracting Activity. II. Synthesis of Isoflavones and Their Activity to Aphanomyces euteiches Zoospore. Biol. Pharm. Bull. 16:698 (1993)) involves the oxidative rearrangement of 2'-hydroxy-4-methoxy-4-(tetrahydropyran-2-yloxy)chalcone by thallium (III) nitrate trihydrate (TTN) in methanol. In spite of the simplicity of this reaction, the overall method suffers from the fact that three steps are required to prepare the starting material 2'-hydroxy-4-methoxy-4-(tetrahydropyran-2-yloxy)chalcone. The method also has the drawback of selective protection (Miles, C. O., et al., Aust. J. Chem 42:1103 (1989)) and deprotection of one of the hydroxyl groups in ring A (benzene ring) of the chalcone. Even with the best method available (Alcantara, A. R., et al., Tetrahedron Letters 28:1515 (1987)) for the condensation of 2-hydroxy-4-(tetrahydropyran-2-yloxyl)acetophenone and p-anisaldehyde the yield was only 64%. Further, this methodology has serious drawbacks such as (a) the use of an expensive and very toxic reagent, thallium (III) nitrate trihydrate (TTN) in excess and (b) the low yield (52%) of formononetin which could be obtained in pure form only after column chromatographic purification.
Another known approach used for the synthesis of formononetin is the general method involving the addition of one carbon to 2-hydroxydeoxybenzoins and their cyclization to form isoflavones. The method introduced by Andrew Pelter (Pelter, Andrew, et al., Synthesis, 5:326 (1976)) involves the reaction of 2-hydroxydeoxybenzoins with N,N-dimethylformamide dimethylacetal (dimethoxydimethyl aminomethane) (two equivalents) in dry benzene. Refluxing a mixture of 2,4-dihydroxy-4'-methoxydeoxybenzoin with N,N-dimethylformamide dimethyl acetal in dry benzene for 4 hours gave formononetin in 85% yield. However, the use of the expensive reagent, N,N-dimethylformamide dimethyl acetal and dry benzene as solvent makes this an unattractive method for the commercial production of formononetin.
A modified version of the above method-microwave mediated synthesis of anticarcinogenic isoflavones from soybeans (Chang, Y-C., et al., J. Agric. Food. Chem 42:1869 (1994)) gave 91% in the case of formononetin. However, this method is totally unsuitable for the large scale preparation due to the fact that microwave mediated reactions are efficient so far in very small scale and possibly in gram quantities. This method has the additional disadvantage of using large excess of N,N-dimethylformamide dimethyl acetal and an equal amount of THF and the requirement of a special reaction vessel to carry out the reaction under microwave conditions.
Another reported method (Wahala, K, et al., J. Chem. Soc Perkin Trans I, 3005 (1991)) involving the in situ formation of deoxybenzoin and its conversion to isoflavones required a large excess of borontrifluoride etherate, dry DMF, and methanesulfonyl chloride under argon atmosphere. All of the reactions are in situ. The experimental conditions, workup procedures, the use of large excess of borontrifluoride etherate and purification by column chromatography to obtain the final product make this method unsuitable for large scale preparations.
A different approach utilizing the modified Vilsmeyer-Haack reaction (Kagal, S. A., et al., Tetrahedron Letters, 14:593 (1962)) has the greatest disadvantage due to the formation of polymeric products along with the unreacted starting material and the reaction required heating (.about.120.degree. C.) for 19 hours. The time consumption and laborious purification procedures make this method a poor choice for large scale preparation even though relatively inexpensive reagents like DMF and phosphorous oxychloride are used in the process.
The method involving the use of 1,3,5-triazine (Jha, H., et al., Angew. Chem Int. Ed. Engl, 20:102 (1981)) in glacial acetic acid, borontrifluoride etherate and acetic anhydride gave formononetin in 91% yield. However, the purification by column chromatography and the use of expensive reagents like 1,3,5-triazine (2 equivalents) makes this method unsuitable for commercial scale production of formononetin.
2,4-Dihydroxy-4'-methoxydeoxybenzoin was prepared by the Fridel Crafts acylation of resorcinol with p-methoxyphenylacetic acid and borontrifluoride etherate in excess. In this reaction, BF.sub.3 etherate was used as a Lewis acid and the solvent for the reaction (Wahala, K., et al., J. Chem. Soc. Perkin Trans I, 3005 (1991)). Another known procedure involved the Hoesch reaction (Organic Synthesis, Collective Volumes, Volume II, P-522, Organic Reactions 5:387 (1949)) of resorcinol with p-methoxyphenyl acetonitrile. However, this procedure is laborious, time consuming and gives poor yield of deoxybenzoin.
A number of methods are available for the preparation of p-methoxyphenylacetic acid and almost all published processes deal with the initial preparation of p-methoxyphenylacetonitrile (Synthesis of p-Methoxyphenylacetonitrile, organic Synthesis, Collective Volumes, Volume IV John Wiley & Sons, Inc. P-576, (1963)) followed by it's hydrolysis. p-Methoxyphenylacetonitrile has been prepared from either methoxybenzyl alcohol or methoxybenzene or p-methoxybenzaldehyde to form p-methoxy benzyl chloride which is then treated with sodium cyanide. Since more than three steps are involved and each step yielding the product in 50-95%, the overall yield of p-methoxyphenyl acetic acid is always less than 60%. These procedures also have the disadvantage of using toxic materials like sodium cyanide, long reaction times and cumbersome isolation procedures. Another known procedure is by the modified Willgerodt reaction (U.S. Pat. No. 5,149,866, Chemical Abstracts 118:38593 (1993); Schwenk, E., et al., J. Org. Chem 11:798 (1946)) which involves the initial preparation of thioacetomorpholide from p-methoxyacetophenone and it's hydrolysis to form p-methoxyphenyl acetic acid. The thioacetomorpholide is prepared by refluxing a mixture of p-methoxy acetophenone, sulfur and morpholine and the hydrolysis is done by refluxing the thioacetomorpholide with alcoholic sodium hydroxide (10 hours) followed by acidification. The product is extracted with diethyl ether and recrystallized from dilute alcohol or water. A reduction in reaction time and the modification of experimental procedures would make this process a better method for the preparation of p-methoxyphenylacetic acid.